Université de Montréal

Stéphane Barakat, Postdoc

Supervisor: Trang Hoang, IRIC

Project title: ETO2, a new actor in the control of the hematopoetic stem cell fate and in T acute lymphoblastic leukemia development

ETO2, known as a transcriptional repressor, belongs to transcriptional complexes containing transcription factors such as SCL, HEB and E2A, which are involved in pediatric leukemia. The project concerns the identification of new functions of ETO2, in the normal and leukemic hematopoietic stem cell fate.

Audrey Carrière-Pazat, Postdoc

Supervisor: Philippe Roux, IRIC

Project title: Determining the role of Ras/MAPK pathway as an upstream regulator of mTOR in acute myeloid leukemia

Leukemic cells often display hyperactivation of themTOR signaling pathway, which highly contributes to their uncontrolled proliferation; however, the mechanisms at the origin of this deregulation remain unknown.We propose to study the role of oncogenic Ras signalling in mTOR hyperactivation, and to determine the molecular links connecting these two major pathways.

The ERK1/ERK2MAP kinases are often up-regulated or activated in solid tumors and leukemias, suggesting an implication of the pathway in the pathogenesis of cancer. In this project, we propose to define the specific functions of ERK1 and ERK2MAP kinases in the control of cell proliferation, differentiation and tumorigenesis.

Hematopoietic cell graft can result in GVHD, and the cytokine TGF-beta has been shown to be protective of that outcome. Our project will analyze the protective function of TGF-beta on the onset of GVHD. Furthermore, we will explore the stimulatory mechanisms allowing lymphocytes and leukemic cells to break the TGF-beta-mediated inhibition and tolerance.

Surapong Koonpaew, Postdoc

Supervisor: Marc Therrien, IRIC

Chromosomal translocations have been linked to leukemia. These translocations often result in the production of oncoproteins (such as NUP98-HOXA9), which cause acute myeloid leukemia in humans and mice that participate in disease development and progression. We plan to use fruit flies expressing NUP98-HOXA9 in a genetic screen to identify new partners of NUP98-HOXA9 activity.

Failure to regulate the self-renewal process of Hematopoietic Stem Cells (HSC) leads to leukemia. My project aims to study the role of Notch in Wnt4 mediated expansion of HSCs. This will be an important step in understanding HSC self-renewal, which will ultimately lead to the development of new strategies to cure leukemia.

Deubiquitination is emerging as an important determinant in carcinogenesis. The deubiquitinase BAP1 (BRCA1-Associated Protein 1) and its associated proteins are firmly implicated in acute myeloid leukemia (AML).We plan to define the molecular mechanisms that govern BAP1 function as well as determining the defects in BAP1 signaling that might contribute to the pathogenesis of AML.

McGill University

Project title: Reversing chemoresistance of AML by targeting the initiation step of translation

AML is a very difficult hematological cancer to manage. Traditional chemotherapy provides only temporary management.We aim to target the mTOR signaling pathway in AML with new chemical inhibitors to assess the potential of these to synergize with standard of care agents.

Project title: Study of the role of the CUX1 protein in leukemia using transgenic mouse models

The CUX1 transcription factor is involved in cancer development, as well as the differentiation of various types of cells, including hematopoietic cells. In this project I will study the role of CUX1 in leukemia development using transgenic mice that over-express CUX1 in the hematopoietic compartment.

Telomerase is an enzyme that is active in 85% of cancers including child leukemia. In order to discover improved therapeutic targets, it is important to understand this enzyme and its regulation. We propose to identify, characterize and validate novel telomerase associated proteins which could serve as potential anticancer targets.

Acute promyelocytic leukemia (APL) provides a model of a malignancy that can be successfully treated by an agent, retinoic acid (RA), targeted directly towards the product of a chromosomal translocation. My project aims to identify and characterize a novel co-repressor complex, whose repression of RA-mediated gene transcription and differentiation of APL cells may represent a general mechanism of resistance to therapy.

My research is concerned with defining mechanisms of apoptosis in acute myeloid leukemia in response to histone deacetylase inhibitors (HDACi). HDACi have shown promising results for the treatment of hematological malignancies and an understanding of their mechanisms of action may help identify novel therapeutic targets for combination therapies with HDACi.